p-oxazinylmethyl-benzodioxane and a process for their manufacture



Patented Dec.26,1944

UNITED STATE all p-OXAZINYLM ETHYL-EENZODIOXANE A PROCESS FOR THEIR MANUFACTURE Adolf Griin, Basel, Switzerland, assignor to the Swissfirm of J. RrGeigy A. G.,'Basel, Switzerland No Drawing. Application February 1943, Serial No. 474,874. In Switzerland January 7, 1942 4 Claims. (01. 260-247) I It has been found that by the interaction of p-oxazine (morpholine) with esters of the 2-hy droxymethyl-benzo-l:4-dioxane there is obtained a base which-preferably in form of a salt or double salt-is therapeutically active and shows new and additional effects or applicability respectively. Esters of inorganic acids,such as of hydrochloric and hydrobromic acid, of sulfuric and phosphoric acid, as well as esters of or- .ganic acids, e. ofarylsulfonic acids,.may be i used. Their preparation is carried out according tousual methods from the acids or their halides and hydroxymethyl-benzodioxane. This intermediate product may be 1produced from pyrocatechine and epichlorhydrine by heating or melting the same under pressure with potassium.

white crystals; M..P. 77 c.; B. P. 153' c. at 1 i hydroxide (Lindemann, Ber. 24, 2149; Fourneau,

.Z pharm. ['7] 198, [8] 18,185) or from diosodium pyrocatechinate with dibrcrnopropyl alcohol (Moureu, Comptes Rendus 126, 1427; Annales de.

Chimie [7] 18, 93). It is however more advantageous to intermix without heating an alkaline pyrocatechine solution with glycerine-epichlor hydrine (or epibromhydrine); i

It is already known that tertiary amines are 1 obtained by reacting 2-chloromethyl-benzodioxane with secondary amines such as dimethyl .amine, piperidine and the like. The said tertiary amines, however; are primarily characterized by a sympathicolytic effect. On the other hand, the oxazinyl derivative shows a greater range of activity; it has valuable narcotic, hypnotic and analgetic properties and exhibits less or no disturbing by-effects respectively. Moreover the oxazinyl derivative is applicable in any formof application.

The present invention is lowing example without being limited thereto.

The parts are by weight.

, Example Equal parts of 2-chloromethyl-benzo l:4-'dioxane, morpholine and benzene are heated inthe autoclave for 10-12 hours to about 150 C. The bases are extracted from the solution by means of diluted sulfuric acid and, after having separated little residues of neutral, substance by shak-' ing out with organic solvents, the bases are again precipitated in the cold by means of sodiumcarbonate. The morpholine not consumed is sepa rated by washing out or distillation-and then regenerated. Thus the nearly pure product is obtained in yields of 85-95%.

Instead of the chlorine compound the equivalent quantity of the bromine compound, 1. e. about illustrated by the fol- 125 wa instead of 100 parts of the chlorine derivative, may be used; in this case a lower temperature may be employed. Likewise hydroxymethyl-benzodioxane esters of organic acids can be used. By recrystallisation or fractionation in vacuo '2-p-oxaziny1methyl-5:6- rbenzo-lz l-dioxane is obtained in a pure form;

mm. pressure. The base gives well crystallising salts, e. g. the hydrochloride, which melts at 212 C. 1 i l l The benzodioxane derivative serving as starting material may be prepared'as follows:

To a cold solution of 220 parts of pyrocatechine in 930 parts of about 12% caustic potash lye are added 225 parts of epichlorhydrine and the mixture is then vigorously shaken, whereupon the reaction takes place after a short time with selfpoint of 154l55 C. at 12 mm. pressure.

heating. Shaking is continued without heating until the alkali is practically nearly completely consumed, then the reaction" product thus precipitated is separated from the upper solution, purified bywashing, drying and distilling.

Thus 270-280 parts of the hydroxymethyl compound are obtainedin form of white crystals having a melting point of 86, C. and a boiling y boiling with concentrated hydrobromic acid and byseparation ofthe remaining quantities of the non-converted product by means of benzine or the like the :bromomethyl compound, a. colorless liquid, is obtained; boiling ,point 126- 127 C. at 0.9 mm. pressure; by treatment with thionylchloride the chloromethyl compound (B. P. is m sha is produced. The chlorides o1 pol ybasic acids azinylmethyl-5 G-benzo-l :4-dioxane by interacting morpholine with an ester of 2-hydroxymethyl-benzodioxane. i

l 2. A process for the manufactureci 2-p-oxazinylmethyl-5 6-benzo-- 1 4-dioxane by interact ing morpholine with a 2-jhalogenomethyl-benzodioxane.

3. A process for the manufacture of z-p-oxazinylmethyl-S:6-benzo-1z4-dioxane by interactbeing white crystals of the melting point 77 C. ing morpholine with 2-chloromethy1benzodioxand the boiling point 153 C. at l mm. pressure, ane. showing valuable narcotic, hypnotic and anal- I 4. The 2-p-oxaziny1methy1-5:S-benzo-l:4-digetic properties.

oxane of the formula 5 0 GHQ-CH,

cE- ,-'cH,-N o

H: CHI-C ADOLF GRfiN. 

